Background

Accumulating evidence suggests that thiazolidinediones (TZDs) may exert protective effects in atrial fibrillation (AF). The present meta-analysis investigated the association between TZD use and the incidence of AF in diabetic patients.

Methods

Electronic databases were searched until December 2016. Of the 346 initially identified records, 3 randomized clinical trials (RCTs) and 4 observational studies with 130,854 diabetic patients were included in the final analysis.

Results

Pooled analysis of the included studies demonstrated that patients treated with TZDs had approximately 30% lower risk of developing AF compared to controls [odds ratio (OR): 0.73, 95% confidence interval (CI): 0.62 to 0.87, p = 0.0003]. This association was consistently observed for both new onset AF (OR =0.77, p = 0.002) and recurrent AF (OR =0.41, p = 0.002), pioglitazone use (OR =0.56, p = 0.04) but not rosiglitazone use (OR =0.78, p = 0.12). The association between TZD use and AF incidence was not significant in the pooled analysis of three RCTs (OR =0.77, 95% CI = 0.53–1.12, p = 0.17), but was significantly in the pooled analysis of the four observational studies (OR =0.71, p = 0.0003).

Conclusions

This meta-analysis suggests that TZDs may confer protection against AF in the setting of diabetes mellitus (DM). This class of drugs can be used as upstream therapy for DM patients to prevent the development of AF. Further large-scale RCTs are needed to determine whether TZDs use could prevent AF in the setting of DM.

Atrial fibrillation (AF) is the most prevalent arrhythmia observed in clinical practice, and is associated with significant morbidity and mortality in the popuation. The burden of AF increases over time mainly due to an aging population and to the increasing prevalence of cardiovascular comorbidities. However, strategies to predict and prevent AF are not fully effective [1]. Diabetes mellitus (DM) is one of the strongest independent risk factors for AF incidence, conferring an approximate 40% higher risk of subsequent AF development [2, 3]. It also predicts the recurrence of AF following a successful direct current cardioversion [4]. Moreover, DM increases the risk of developing stroke, heart failure, and cardiovascular death in patients with AF [5]. Although the exact pathophysiological mechanisms linking DM and AF remain incompletely elucidated, an increasing body of evidence suggests that inflammation and oxidative stress may play an important role [6, 7, 8].

This systematic review was conducted according to the Quality of Reports of Meta-Analyses of Randomized Controlled Trials (QUOROM) recommendations [19] and the guidelines of the Meta-analysis of Observational Studies in Epidemiology Group (MOOSE) [20].

Inclusion criteria

The studies considered for this meta-analysis were either randomized clinical trials (RCTs) or observational studies that investigated the potential effects of TZDs on AF. The inclusion criteria were as follows: RCTs: 1) randomized controlled human trials with a parallel design; 2) comparison of TZDs with control; 3) collecting data on new or recurrent AF during follow-up. Observational Studies: 1) comparison of TZDs with control; 2) evaluating new or recurrent AF as an outcome. In the studies of interventions with TZDs no limit in the length of follow-up period was set due to the paucity of relevant studies.

Search strategies

A systematic literature search was performed by two investigators (Z. Z. and X. Z.) using the online databases of PubMed and Embase to identify relevant studies published before December 2016. The following key terms were used: “thiazolidinediones”, “pioglitazone”, “rosiglitazone”, “troglitazone”, and “atrial fibrillation”. Both investigators independently evaluated the search results and identified potential studies for further assessment. Disagreements were resolved by a third reviewer (T. L.).

Quality assessment and data extraction

As quality scoring in meta-analyses of RCTs and observational studies is controversial, several key points of study quality were assessed according to a critical review checklist of Wynn et al. [
21]. The key points of this checklist and quality assessments of included studies are listed in Table
1.

Two investigators (Z. Z. and X. Z.) independently extracted the relevant data using a pre-defined spreadsheets. The extracted data elements of the meta-analysis included information on the inclusion criteria, publication details, study design, follow-up duration, daily dosage of TZDs, definition of AF, methods of AF detection, baseline patient characteristics, the variables of multivariate model used in observational studies and results. Disagreements were resolved through discussion or consensus with a third reviewer (T. L.).

Statistical analysis

Results of the AF outcome are expressed as odds ratio (OR) with 95% confidence interval (CI) for each study using generic inverse-variance method. The hazard ratio value using multivariate Cox proportional hazards model in the primary study was directly considered as OR [22]. Raw event numbers were extracted from the RCTs and adjusted effect estimates from the observational studies to calculate the overall effects. Statistical heterogeneity was assessed by the χ2 test and quantified by using the I2 statistic. An I2 > 50% is indicative of at least moderate heterogeneity [23]. A random-effects model was used. Subgroup analyses regarding AF subtypes (new onset AF or recurrent AF), different TZDs (solely pioglitazone or solely rosiglitazone), study designs (RCTs or observational studies), and different follow-up duration (>5 years or ≤5 years) were additionally performed. Sensitivity analysis was done by removing one study at a time and checking the consequent effects on the effect estimate. Publication bias was evaluated using a funnel plot. Two-tailed p values of <0.05 were considered statistically significant. The statistical analysis was performed using the Review Manager (RevMan, version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

The main findings of this comprehensive meta-analysis on 130,854 diabetic patients are the following: i. TZDs may confer protection against AF incidence; ii. the beneficial effects of TZDs were consistently observed in both new onset and recurrent AF; iii. Pioglitazone use was associated with a statistically reduced risk of incident AF, whereas rosiglitazone use showed no statistically significant difference; and iv. the protective effects of TZDs were only observed in the pooled analysis of the observational studies rather than the RCTs.

Moreover, in the present meta-analysis, we observed that pioglitazone use was associated with beneficial effects on AF prevention compared with rosiglitazone use. Similarly, previous study suggested that pioglitazone has a beneficial effect on cardiovascular disease, whereas rosiglitazone seemed to increase cardiovascular risk [24]. By assembling a diabetic cohort of older than 65 years, Winkelmayer et al. [25] demonstrated greater risk of mortality and congestive heart failure among patients who initiated therapy with rosiglitazone compared with pioglitazone, however, there were no differences in their incidences of myocardial infarction or stroke. Previous data [26] also showed similar effects on glycemic control between pioglitazone and rosiglitazone, as well as on other parameters such as C-reactive protein (CRP), plasminogen activator inhibitor-1 and indices of insulin secretion and sensitivity. However, pioglitazone treatment was associated with greater beneficial changes on plasma lipids than rosiglitazone treatment [26], which may partly explain the advantage of pioglitazone in reducing AF incidence.

Recently, the IRIS trial [27] demonstrated that pioglitazone can prevent fatal or nonfatal stroke or myocardial infarction among patients who have insulin resistance along with cerebrovascular disease. However, the underlying mechanism for these beneficial effects of pioglitazone remains incompletely elucidated. AF is a known risk factor of morbidity and mortality by predisposing to strokes and acute coronary syndrome [28]. Thus, it is possible to postulate that pioglitazone reduces the stroke or MI events partly through the reduction of AF burden.

Accumulating evidence supports the role of inflammation and immune response activation in the genesis and perpetuation of AF in different clinical settings, including cardiac surgery, electrical cardioversion and catheter ablation [Women's fitflop Scoop Silver F K36 Performance Sporty Cut Sneaker pqFrp5n]. Oxidative stress has been suggested to play an important role in AF incidence [30]. Numerous studies have demonstrated that TZDs may attenuate inflammation and oxidative stress as well as atrial electrophysiological and structural remodeling in different animal models.

Finally, the treatment of hyperglycemia may have favorable effects on AF burden. In other words, treatment of DM may ameliorate atrial remodeling [7]. Haemoglobin A1c levels have been associated with the occurrence and recurrence of AF [7, 39, 40], and therefore TZDs may exert their favorable effects through HbA1c level reduction.

Study limitations

The present meta-analysis has potential limitations. Firstly, due to the small number of included studies we analyzed observational studies and RCTs together while 2 included RCTs reported AF as an adverse event rather than a predefined endpoint, and the favorable effects of TZDs use on preventing AF incidence were predominately driven by observational studies, whereas data from the 2 RCTs were unable to draw unanimous conclusion. Secondly, information regarding methods of AF detection, cardiac substrate, ejection fraction and atrial volume were not fully presented in our analysis due to the lack of relative data. Thirdly, the heterogeneous types of patient populations (ranging from uncomplicated type 2 diabetics to post-CABG or post-AF ablation patients) may indicate latent bias in this meta-analysis. Fourthly, “gray” literature (primarily conference abstracts/presentations, ongoing studies, communication with investigators) was not searched. Finally, the results of the funnel plot suggested that publication bias may be present, although the small number of studies made this somewhat difficult to interpret (Fig.
3).

In summary, this meta-analysis suggests that TZDs may be effective in AF prevention in the setting of DM. Therefore, TZDs may be considered as the treatment of choice in diabetic patient with high risk features for AF incidence. Since the overall conclusion was mainly drawn from the observational studies, further large-scale prospective RCTs that assessed AF as a predefined outcome are needed to determine whether TZDs use could prevent AF in the setting of DM.

Acknowledgments

Funding

This work was supported by grants (81,570,298, 30,900,618, 81,270,245 to T.L.) from the National Natural Science Foundation of China, Tianjin Natural Science Foundation (16JCZDJC34900 to T.L.).

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Authors’ contributions

ZZ and ZX participated in study design, searched databases, extracted and assessed data, carried out the statistical analysis and drafted the manuscript. LM and MG performed statistical analyses. TL and GL conceived the design of the study, selected the included studies and drafted the review. KP, KPL and GT revised the manuscript. All authors read and approved the final manuscript.

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